The present invention relates to novel compounds, which are derivatives of ureas, thioureas, carbamates, sulfonylureas, sulfonamides, amides, and thioamides of 2-carboxyindoles. The invention also relates to methods for the preparation of the novel compounds, as well as to pharmaceutical compositions or methods of use for the novel compounds. More specifically, the compounds of the present invention are useful in the treatment of neurodegenerative disorders including cerebrovascular disorders as well as in the treatment of schizophrenia or epilepsy; and as analgesics and anxiolytics.
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this neurodegeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at N-methyl-D-aspartate (NMDA), .alpha.-amino-3-hydroxy -5-methyl-isoxazole propionic acid (AMPA), and kainate receptors. This excitotoxic action is responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma.
There are no specific therapies for these neurodegenerative diseases; however, compounds which act specifically as antagonists of EAA receptors and in particular the NMDA receptor complex, either competitively or noncompetitively, offer a novel therapeutic approach to these disorders: R. Schwarcz and B. Meldrum, The Lancet 140 (1985); B. Meldrum in "Neurotoxins and Their Pharmacological Implications" edited by P. Jenner, Raven Press, New York (1987); D. W. Choi, Neuron 1:623 (1988). Confirmation of the protective effects of noncompetitive NMDA antagonists in various pharmacological models of neurodegenerative disorders have appeared in the literature: J. W. McDonald, F. S. Silverstein, and M. V. Johnston, Eur. J. Pharmacol. 140:359 (1987); R. Gill, A. C. Foster, and G. N. Woodruff, J. Neurosci. 7:3343 (1987); S. M. Rothman, J. H. Thurston, R. E. Hauhart, G. D. Clark, and J. S. Soloman, Neurosci. 21:673 (1987); M. P. Goldbert, P-C. Pham, and D. W. Choi, Neurosci. Lett. 80:11 (1987); L. F. Copeland, P. A. Boxer, and F. W. Marcoux, Soc. Neurosci. Abstr. 14 (part 1):420 (1988); J. A. Kemp, A. C. Foster, R. Gill, and G. N. Woodruff, TIPS 8:414 (1987); R. Gill, A. C. Foster, and G. N. Woodruff J. Neurosci. 25:847 (1988); C. K. Park, D. G. Nehls, D. I. Graham, G. M. Teasdale, and J. M. McCulloch, Ann. Neurol. 24:543 (1988); G. K. Steinburg, C. P. George, R. DeLaPlaz, D. K. Shibata, and T. Gross, Stroke 19:1112 (1988); J. F. Church, S. Zeman, and D. Lodge, Anesthesiology 69:702 (1988).
U.S. Pat. No. 4,960,736 discloses certain 2-carboxy indole derivatives useful as excitatory (EAA) amino acid antagonists and EP Application Numbers 90107633.1 and 90108337.8 also disclose certain 2-carboxy indole derivatives for use to treat neurotoxic injury or neurodegenerative diseases known to be caused by or accelerated by certain EAAs found in the central nervous system (CNS).
U.S. Pat. No. 3,472,870 (Derwent Abstract No. 37,778), U.S. Pat. No. 3,364,224 (Abstract No. 30,396), teach sulphamidotryptamines and .beta.-carbolines, respectively, differing by their failure to show the R.sup.1, R.sup.2, R.sup.3, and R.sup.4 substituents and amide linkage of the present invention. U.S. Pat. No. 3,182,071 (Derwent Abstract No. 16,591) discloses acylated indoles also differing in substituents and amide linkages.
U.S. Pat. No. 3,574,737 teaches iminocarbamic acid ester derivatives including a benzopyrrole(indole) substrate having urea-like substituents but without an amido linkage as a fungicide.
Additionally, U.S. application Ser. No. 07/670,860, filed Mar. 18, 1991, which is copending to the present application, teaches amides of indoles, thus differing from the present invention with amine-type substituents on indoles. Other references include 1) J. Med. Chem. 1991, Vol. 34, No. 4, pp. 1243+ and (2) J. Med. Chem. 1991, Vol. 34, No. 4, pp. 1283+. The first of these J. Med. Chem. disclosures includes a 2-carboxyindole which differs from the present invention by the lack of a 3-substituent. The second J. Med. Chem. disclosure features various indole dicarboxylate derivatives but, particularly, does not provide the 3-substituent of the present invention.
In Abstract No. 9 and paper entitled "Novel Glycine Antagonists", presented at the 201st Annual American Chemical Society Meeting at Atlanta, Ga., on Apr. 14-19, 1991, Medicinal Chemistry Section, teach a urea substituent on a substrate that is not an indole.
Science, 1989, Vol. 243, page 1611 describes selected 2 carboxyindoles which antagonize the strychnine insensitive glycine site of the NMDA receptor. The disclosed 2-carboxyindoles do not suggest the amide derivatives of the present invention.
PCT/DK90/00257 discloses indole derivatives having CNS activities differing in structure from the present invention by the substituents thereon.
However, although the present invention is also 2-substituted indoles, none of these references teaches the substituent represented by ANR.sup.5 R.sup.6 in the present invention. The compounds of this application are 2-carboxyindoles and derivatives thereof having as substituents, for example, hydroxamide, amide, urea amide, ester amide, or sulphonamide.